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NEUROLOGY
DOI: 10.1212/WNL.0000000000009619
Miller Fisher Syndrome and polyneuritis cranialis in COVID-19
Consuelo Gutiérrez-Ortiz, MD, PhD;1, 2 Antonio Méndez, MD;3 Sara Rodrigo-Rey, MD;1
Eduardo San Pedro-Murillo, MD;3 Laura Bermejo-Guerrero, MD;3 Ricardo Gordo-Mañas,
MD;4 Fernando de Aragón-Gómez, MD;1
Julián Benito-León, MD, PhD3,5,6
Department of Glaucoma and Neuro-Ophthalmology,1 University Hospital “Príncipe de Asturias”,
Alcalá de Henares, Madrid, Spain; Department of Glaucoma,2 ”Martínez de Carneros” Clinic,
Madrid, Spain; Department of Neurology,3 University Hospital “12 de Octubre”, Madrid, Spain;
Department of Neurology,4 University Hospital “Príncipe de Asturias”, Alcalá de Henares, Madrid,
Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
(CIBERNED),5 Madrid, Spain; Department of Medicine,6 Universidad Complutense, Madrid, Spain
Corresponding author: Julián Benito-León ([email protected])
Word Count: 241 (abstract); 1,301 (text); 11 references; 0 figures; 0 tables.
Keywords: Anosmia, Ageusia, COVID-19, Miller Fisher Syndrome, polyneuritis cranialis,
SARS-CoV-2.
Published Ahead of Print on April 17, 2020 as 10.1212/WNL.0000000000009619
Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Acknowledgment
We thank Dr. Elan D. Louis for the editing and proof reading of the manuscript.
Study Funding:
This research was supported by FEDER funds.
Disclosure:
C. Gutiérrez-Ortiz, A. Méndez, S. Rodrigo-Rey, E. San Pedro-Murillo, L. Bermejo-
Guerrero, R. Gordo-Mañas, and F. de Aragón-Gómez report no relevant disclosures. J.
Benito-León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS
#R01 NS39422), European Commission (grant ICT-2011-287739, NeuroTREMOR), the
Ministry of Economy and Competitiveness (grant RTC-2015-3967-1, NetMD—platform for
the tracking of movement disorder), and the Spanish Health Research Agency (grant FIS
PI12/01602 and grant FIS PI16/00451).
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Abstract
Objective: To report two patients infected with severe acute respiratory syndrome
coronavirus-2 (SARS-CoV-2) who acutely presented with Miller Fisher syndrome and
polyneuritis cranialis, respectively.
Methods: Patient data were obtained from medical records from the University Hospital
“Príncipe de Asturias”, Alcalá de Henares, Madrid, Spain and from the University Hospital
“12 de Octubre”, Madrid, Spain.
Results: The first patient was a 50-year-old man who presented with anosmia, ageusia,
right internuclear ophthalmoparesis, right fascicular oculomotor palsy, ataxia, areflexia,
albuminocytologic dissociation and positive testing for GD1b-IgG antibodies. Five days
before, he had developed a cough, malaise, headache, low back pain, and a fever. The
second patient was a 39-year-old man who presented with ageusia, bilateral abducens
palsy, areflexia and albuminocytologic dissociation. Three days before, he had developed
diarrhea, a low-grade fever, and a poor general condition. The oropharyngeal swab test
for coronavirus disease 2019 (COVID-19) by qualitative real-time reverse-transcriptase–
polymerase-chain-reaction assay was positive in both patients and negative in the
cerebrospinal fluid. The first patient was treated with intravenous immunoglobulin and the
second, with acetaminophen. Two weeks later, both patients made a complete
neurological recovery, except for residual anosmia and ageusia in the first case.
Conclusions: Our two cases highlight the rare occurrence of Miller Fisher syndrome and
polyneuritis cranialis during the COVID-2 pandemic. Neurological manifestations may
occur because of an aberrant immune response to COVID-19. The full clinical spectrum of
neurological symptoms in patients with COVID-19 remains to be characterized.
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Coronavirus belongs to a family of single-stranded RNA viruses,1 which includes
the severe acute respiratory syndrome coronavirus (SARS-CoV)2 and the Middle East
respiratory syndrome coronavirus (MERS-CoV).3 A new coronavirus, SARS-CoV-2, has
rapidly spread throughout China and other countries, representing a global public health
concern.
SARS-CoV-2 is a highly pathogenic virus, and the understanding of its
epidemiology, natural history, transmission, clinical presentation, and therapeutics is
currently evolving. The spectrum of the coronavirus disease 2019 (COVID-19) ranges
from asymptomatic infection to severe respiratory failure; fever, cough, fatigue, sputum
production, shortness of breath, myalgias or arthralgias, and sore throat are among its
most common manifestations.4 Other less common features, such as gastrointestinal
(e.g., diarrhea, nausea, and vomiting) or even neurological manifestations (e.g.,
headache) have also been reported. In addition, other neurological symptoms such as
anosmia and ageusia are presented by many patients.5 However, the knowledge of the
clinical features and pathogenesis of COVID-19 still needs to be elucidated. Specifically,
the exact nature and mechanism of COVID-19-induced neurological manifestations
largely remains unknown. In this sense, different neurological complications have been
reported with its predecessors. The SARS-CoV was occasionally associated with the
development of different neurological manifestations including axonopathic
polyneuropathy, myopathy, rhabdomyolysis and large artery ischemic stroke, among
others.6 During or after MERS-CoV treatment, Bickerstaff's encephalitis overlapping with
Guillain-Barré syndrome, intensive-care-unit-acquired weakness, or other toxic or
infectious neuropathies have been reported.7
We herein report two patients infected with SARS-CoV-2 who acutely presented
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with Miller Fisher syndrome and polyneuritis cranialis, respectively
METHODS
Patient data were obtained from medical records from the University Hospital “12
de Octubre”, Madrid, Spain and from the University Hospital “Príncipe de Asturias”, Alcala
de Henares, Madrid, Spain.
Standard Protocol Approvals, Registrations, and Patient Consents
Written informed consent was obtained from two patients participating in the study
(consent for research).
Data Availability
The data supporting the findings of this study are available within the article.
RESULTS
Patient 1. A 50-year-old man was admitted to the emergency room of the University
Hospital “12 de Octubre”, Madrid, because of a 2-day history of vertical diplopia, perioral
paraesthesias and gait instability. His past medical history was remarkable for bronchial
asthma. Five days prior to his visit, he had developed a cough, malaise, headache, low
back pain, and a fever. He did not report nausea, vomiting, sensory deficits or urinary
incontinence, but noted the presence of anosmia and ageusia. Except for a temperature
of 99.9ºF, his vital signs were normal (pulse 72; blood pressure 132/68 mm Hg and basal
oxygen saturation of 98%). Pulmonary and cardiac auscultation and abdominal
examination were also unremarkable.
The neurological examination revealed that cognitive function and language were
intact. He complained of perioral paresthesias, but no facial weakness was observed.
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Strength and muscle tone were normal in all extremities, and no sensory deficits were
detected. He had a broad-based ataxic gait. There was no dysmetria on finger-to-nose
and heel-to-shin tests. Muscle stretch reflex examination revealed absent deep tendon
reflexes in the upper and in the lower limbs. The plantar responses were flexor bilaterally.
The neuro-ophthalmological examination revealed visual acuity of 20/25 in both eyes. The
anterior poles, intraocular pressure and fundi were normal, and the optic nerves did not
show disk edema. His pupils reacted briskly to light, without a relative afferent pupillary
defect. There was no ptosis. He showed right hypertropia in all fields of gaze, severe
limitations to the adduction and downgaze movements of his right eye, and left eye
nystagmus on left gaze. All these findings were consistent with right internuclear
ophthalmoparesis and right fascicular oculomotor palsy. No orbicularis weakness,
variability or fatigability was noted.
The blood work‐up revealed lymphopenia (1000 cells/ul) and elevated C-reactive
protein (2.8 mg/dl). The antibodies to gangliosides (GM1, GM2, GM3, GD1a, GD1b, GD3,
GT1a, GT1b, GQ1b, and anti-sulfatide antibodies) in the serum were examined. He was
only positive to the antibody GD1b-IgG. The patient’s oropharyngeal swab test for COVID-
19 by qualitative real-time reverse-transcriptase–polymerase-chain-reaction (rRT-PCR)
assay was positive. The cerebrospinal fluid (CSF) examination revealed an opening
pressure of 11 cm of H2O, white blood cell count = 0/μl, protein = 80 mg/dl, glucose = 62
mg/dl, with normal cytology, sterile cultures and negative serologies, including the rRT-
PCR for COVID-19. Chest X-ray and head computerized tomography without contrast
were normal.
He was treated with intravenously administered immunoglobulin 0.4 g/kg for 5 days
starting on the fifth day of his neurological symptoms. The cranial neuropathies and the
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ataxia improved significantly over the succeeding days and he was discharged home two
weeks after admission, with a resolution of the neurological features, except for residual
anosmia and ageusia.
Patient 2. A 39-year-old man was admitted to the emergency room of the University
Hospital “Príncipe de Asturias”, Alcalá de Henares, Madrid because of acute onset
diplopia. His past medical history was unremarkable. Three days before, he had
presented with diarrhea, a low-grade fever, and a generally poor condition, without any
headache, respiratory symptoms or dyspnea. He did not report nausea or vomiting but
noted the presence of ageusia. On examination, his body temperature was 96.3°F, pulse
74, blood pressure 125/72 mmHg and basal oxygen saturation 98%. Respiratory,
cardiovascular, and abdominal examinations were also normal. On neurological
examination, the patient was conscious, alert and well oriented to time, place, and person.
The neuro-ophthalmological examination revealed visual acuity of 20/25 in both eyes. The
anterior poles, intraocular pressure, and the fundi were normal without disk edema. His
pupils were normal. He showed esotropia of 10 prism diopters at distance and 4 prism
diopters at near, severe abduction deficits in both eyes, and fixation nystagmus, with the
upper gaze more impaired, all consistent with bilateral abducens palsy. No orbicularis
weakness, variability or fatigability was noted. All deep tendon reflexes were absent; the
remainder of the neurological examination of limbs, including sensation, was normal. No
gait instability or truncal ataxia was observed. Finger-to-nose and heel-to-shin tests
showed no dysmetria or decomposition.
Routine blood tests as well as those for liver function, renal function, myocardial
enzymes, and electrolytes were normal, but leukopenia was present (3100 cells/ul). The
patient’s oropharyngeal swab test for COVID-19 by qualitative rRT-PCR assay was
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positive. The CSF examination revealed an opening pressure of 10 cm H2O, white blood
cell count = 2/μl (all monocytes), protein = 62 mg/dl, glucose = 50 mg/dl, with normal
cytology, sterile cultures and negative serologies, including the rRT-PCR for COVID-19.
Chest X-ray and head computerized tomography without contrast were normal.
The patient was discharged home and treated symptomatically with acetaminophen
and telemedicine monitoring due to a complete hospital saturation with COVID-19
patients. The anti-ganglioside antibody profile could not be performed because of the
aforementioned hospital saturation. At the next consultation, two weeks later, he had
made a complete neurological recovery with no ageusia, complete eye movements, and
normal deep tendon reflexes.
DISCUSSION
Coronaviruses, in general, share a similar viral structure, and the pathogenic
mechanisms of other coronavirus may also be applicable for SARS-CoV-2. Specifically,
the human receptor for SARS-Cov-2 may be angiotensin-converting enzyme 2 receptor,
similar to that of SARS-CoV.8 A growing body of evidence shows that neurotropism is one
common feature of coronavirus.9 Animal models show that SARS‐CoV and MERS-CoV
might enter the brain, possibly via the olfactory nerves, and thereafter rapidly spread to
specific brain areas including the thalamus and brainstem.9 This might explain the
complaints of anosmia of many patients infected by SARS-Cov-2.5 Furthermore,
inflammatory or immune-associated-molecules, such as cytokines, that are detected in
COVID-19 infected patients, may affect the taste buds and hence cause ageusia.10
Notwithstanding, an understanding of the exact mechanism of coronavirus-induced
neurological symptoms is in its infancy.
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Miller Fisher syndrome is characterized by the acute onset of external
ophthalmoplegia, ataxia, and loss of tendon reflexes. We have described one patient with
COVID-19 infection who had a Miller Fisher syndrome as an unusual initial neurological
manifestation. The second patient did not, however, have classic Miller Fisher syndrome,
but polyneuritis cranialis (or isolated multiple cranial neuropathy) that spontaneously and
rapidly improved. There are however incomplete forms of Miller Fisher, including acute
ataxic neuropathy, which can be diagnosed in the absence of ophthalmoplegia, and acute
ophthalmoparesis, which may occur in the absence of ataxia as in this second patient.11
Nevertheless, polyneuritis cranialis may be a separate subtype altogether, which lies at
the interface between Miller Fisher syndrome and Guillain-Barré syndrome.12
Miller Fisher syndrome has been shown to be preceded by infections similar to
those preceding Guillain-Barré syndrome, suggesting a para- or postviral process.
Haemophilus influenzae, Campylobacter jejuni and cytomegalovirus are the most
common pathogens involved.13 However, to the best of our knowledge, Miller Fisher
syndrome has not been reported associated to the SARS-Cov-2. The occurrence of Miller
Fisher syndrome and polyneuritis cranialis in these two patients with the SARS-CoV-2
infection could be simply coincidental. However, taking into account the temporal
relationship, we feel that COVID-19 might have been responsible for the development of
these two neurological pictures. Further supporting this hypothesis was the recent
publication of a single case report suggesting a possible association between Guillain-
Barré syndrome and SARS-CoV-2 infection.14
The pathogenesis of Miller Fisher syndrome and polyneuritis cranialis in a COVID-
19 infection may include immune mechanisms or direct viral neuropathogenic effects. We
think that the main mechanism was an aberrant immune response. First, in neither of our
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two patients did we detect SARS-Cov-2 in the CSF, suggesting that virus may not be
directly encephalogenic. Second, patients infected with SARS-Cov-2 may show increased
levels of plasma pro-inflammatory cytokines that could be involved in the damage induced
by SARS-Cov-2.15 Third, serum GD1b-IgG antibodies can be detected in Miller Fisher
syndrome,16 and were positive in the first patient, supporting the hypothesis of immune-
mediated injury rather than direct viral neurotropism. Most patients with Miller Fisher
syndrome show GQ1b positivity; however, antibodies to GD1b have been associated with
a faster recovery.16 Finally, there was a significant recovery of the neurological deficit with
the use of intravenous immunoglobulin therapy in the first patient. In this sense,
immunotherapy with intravenous immunoglobulin could be used to neutralize the SARS-
Cov-2 infection. However, its efficacy would be much better if the immune IgG antibodies
were collected from patients who have recovered from SARS-Cov-2 infection in the
surrounding area, in order to increase the chance of neutralizing the virus.17
We recognize that the main limitations of each one of the cases was the absence
of electromyography and nerve conduction studies as well as magnetic resonance
imaging (to detect nerve enhancement). The reason for this was the extreme
circumstances in our hospitals at the peak of this pandemic.
In conclusion, we describe two patients with COVID-19 with Miller Fisher syndrome
and polyneuritis cranialis, respectively, who had good outcomes. We suggest considering
the presence of a COVID-19 infection in those patients with Miller Fisher syndrome or with
polyneuritis cranialis in the setting of the current pandemic. Neurological manifestations
may occur because of an aberrant immune response to COVID-19. At present, the full
clinical spectrum of patients with COVID-19 with neurological symptoms remains to be
characterized.
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APPENDIX 1. AUTHORS
Name Location Contribution
Consuelo Gutiérrez-Ortiz,
MD, PhD
Department of Glaucoma
and Neuro-Ophthalmology,
University Hospital
“Príncipe de Asturias”,
Alcalá de Henares, Madrid,
Spain; Department of
Glaucoma, ”Martínez de
Carneros” Clinic, Madrid,
Spain
Conception, organization
and execution of the
research project; writing of
the first draft and the
review and critique of the
manuscript
Antonio Méndez, MD Department of Neurology,
University Hospital “12 de
Octubre”, Madrid, Spain
Conception, organization
and execution of the
research project; writing of
the first draft and the
review and critique of the
manuscript
Sara Rodrigo-Rey, MD Department of Glaucoma
and Neuro-Ophthalmology,
University Hospital
“Príncipe de Asturias”,
Alcalá de Henares, Madrid,
Spain
Conception and
organization of the
research project; review
and critique of the
manuscript
Eduardo San Pedro- Department of Neurology, Conception and
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Murillo, MD University Hospital “12 de
Octubre”, Madrid, Spain
organization of the
research project; review
and critique of the
manuscript
Laura Bermejo-Guerrero,
MD
Department of Neurology,
University Hospital “12 de
Octubre”, Madrid, Spain
Conception and
organization of the
research project; review
and critique of the
manuscript
Ricardo Gordo-Mañas, MD Department of Neurology,
University Hospital
“Príncipe de Asturias”,
Alcalá de Henares, Madrid,
Spain
Conception and
organization of the
research project; review
and critique of the
manuscript
Fernando de Aragón-
Gómez, MD
Department of Glaucoma
and Neuro-Ophthalmology,
University Hospital
“Príncipe de Asturias”,
Alcalá de Henares, Madrid,
Spain
Conception and
organization of the
research project; review
and critique of the
manuscript
Julián Benito-León, MD,
PhD
Department of Neurology,
University Hospital “12 de
Octubre”, Madrid, Spain;
Centro de Investigación
Biomédica en Red sobre
Enfermedades
Conception, organization,
and execution of the
research project; writing of
the manuscript first draft
and the review and critique
of the manuscript
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Neurodegenerativas
(CIBERNED), Madrid,
Spain; Department of
Medicine, Universidad
Complutense, Madrid,
Spain
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REFERENCES
1. Weiss SR, Leibowitz JL. Coronavirus pathogenesis. Advances in virus research 2011;81:85-164. 2. Chan-Yeung M, Xu RH. SARS: epidemiology. Respirology (Carlton, Vic) 2003;8 Suppl:S9-14. 3. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. The New England journal of medicine 2012;367:1814-1820. 4. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine 2020. 5. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and ageusia: common findings in COVID-19 patients. The Laryngoscope 2020. 6. Tsai LK, Hsieh ST, Chang YC. Neurological manifestations in severe acute respiratory syndrome. Acta neurologica Taiwanica 2005;14:113-119. 7. Kim JE, Heo JH, Kim HO, et al. Neurological Complications during Treatment of Middle East Respiratory Syndrome. Journal of clinical neurology (Seoul, Korea) 2017;13:227-233. 8. Kannan S, Shaik Syed Ali P, Sheeza A, Hemalatha K. COVID-19 (Novel Coronavirus 2019) - recent trends. European review for medical and pharmacological sciences 2020;24:2006-2011. 9. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. Journal of medical virology 2020. 10. Wang H, Zhou M, Brand J, Huang L. Inflammation and taste disorders: mechanisms in taste buds. Annals of the New York Academy of Sciences 2009;1170:596-603. 11. Wakerley BR, Uncini A, Yuki N. Guillain-Barre and Miller Fisher syndromes--new diagnostic classification. Nature reviews Neurology 2014;10:537-544. 12. Wakerley BR, Yuki N. Polyneuritis cranialis—subtype of Guillain–Barré syndrome? Nature Reviews Neurology 2015;11:664-664. 13. Koga M, Kishi M, Fukusako T, Ikuta N, Kato M, Kanda T. Antecedent infections in Fisher syndrome: sources of variation in clinical characteristics. J Neurol 2019;266:1655-1662. 14. Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence? The Lancet Neurology 2020. 15. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of autoimmunity 2020:102433. 16. Taams NE, Notermans NC, Fokkink WR, et al. Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies. Journal of the peripheral nervous system : JPNS 2018;23:227-234. 17. Jawhara S. Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients? International journal of molecular sciences 2020;21.
DOI 10.1212/WNL.0000000000009619 published online April 17, 2020Neurology
Consuelo Gutiérrez-Ortiz, Antonio Méndez, Sara Rodrigo-Rey, et al. Miller Fisher Syndrome and polyneuritis cranialis in COVID-19
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